Roberts Syndrome

NORD is very grateful to Uta Francke, MD, Department of Genetics, Stanford University School of Medicine, for assistance in the preparation of this report.

Synonyms of Roberts Syndrome

Hypomelia-Hypotrichosis-Facial Hemangioma Syndrome

Pseudothalidomide Syndrome

SC Syndrome

Disorder Subdivisions

Phocomelia

General Discussion

Roberts syndrome is a rare genetic disorder characterized by growth delays before and after birth (pre- and postnatal growth deficiency); malformations of the arms and legs (limbs); distinctive abnormalities of the skull and facial (craniofacial) region. Mental retardation occurs in some cases; normal intelligence has also been reported.

In infants with Roberts syndrome, the arms and legs may be incompletely developed (limb reduction abnormalities), however, such limb defects are usually symmetrical which are distinct from the asymmetrical limb defects in CdLS. Such abnormalities may range from absence of all four limbs (tetraphocomelia) to less severe degrees of limb reduction, such as underdevelopment and/or absence of certain bones of the upper arms (humeri), forearms (radii and/or ulnae), thighs (femurs), shins (tibiae), and/or on the outside of the lower legs (fibulae). Characteristic craniofacial abnormalities may include an unusually small, broad head (microbrachycephaly); abnormal grooves on either side of the upper lip (bilateral cleft lip); incomplete development of the roof of the mouth (cleft palate); thin, small wings of the nose (hypoplastic nasal alae); and/or low-set, malformed (dysplastic) ears. Additional abnormalities are often present. Roberts syndrome is probably genetically heterogeneous. While it is inherited as an autosomal recessive trait in most families, the possibility of new mutation in an autosomal dominant gene cannot be excluded.
Initially, researchers believed that Roberts syndrome and SC phocomelia syndrome were separate disorders. However, researchers now believe that the two disorders are different expressions of one distinct disorder because different changes in the same gene are the underlying cause for both conditions.

Symptoms

The symptoms associated with Roberts syndrome vary widely from case to case even among members of the same family. Most infants experience growth deficiencies and have abnormalities of the limbs and craniofacial region. Infants with Roberts syndrome often experience life-threatening complications early in infancy.

Affected infants may experience growth deficiencies before and after birth (pre- and postnatally). Mental retardation is a variable finding that occurs in approximately 50 percent of cases.

Limb abnormalities are common in infants with Roberts syndrome and may range from underdeveloped bones in the arms and legs (hypomelia) to complete absence of all four limbs (tetraphocomelia). The arms are usually more severely affected than the legs.

Additional abnormalities may affect the arms and legs including permanent fixation (contracture) of various joints, especially the knees and elbows. The number of fingers and/or toes may be reduced and the fifth fingers may be in a fixed laterally deviated position (clinodactyly). Webbing of the finger and toes (syndactyly) may also be present. Infants with Roberts syndrome may also have a form of club foot where the heel of the foot may be elevated and turned outward away from the body (talipes equinovalgus).

Infants with Roberts Syndrome also have a variety of craniofacial abnormalities including a small, broad head (microbrachycephaly); an abnormal groove in the upper lip (cleft lip) with or without incomplete closure of the roof of the mouth (cleft palate); a flattened nose with small wings; an abnormally small jaw (micrognathia); sparse, silvery hair; and malformed, low-set ears that often lack lobes. Some infants may experience premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). Affected infants may have eye (ocular) abnormalities including widely spaced eyes (hypertelorism); unusually small eyes (microphthalmia); cloudy corneas; and bulging or prominent eyes (proptosis) due to shallow eye cavities (orbits). In some cases, the whites of the eyes may be blue (blue sclera) and increased pressure within the eyeball (glaucoma) may also be present.

Some infants with Roberts syndrome may have one or more pink or dark red irregularly shaped patches of skin (hemangiomas) on the face caused by dense collections of small blood vessels (capillaries).

Infants with Roberts syndrome often have abnormalities affecting the genitourinary system. Males may have the urinary opening located on the underside of the penis (hypospadias) and the testicles may fail to descend into the scrotum (cryptorchidism). Females may have a malformed uterus with horn-like branches (bicornuate uterus).

Less common symptoms associated with Roberts syndrome include malformed kidneys, an abnormal increase in cerebrospinal fluid resulting in enlargement of the skull (hydrocephalus), paralysis of cranial nerves, seizures, heart defects and a decreased number of blood platelets (thrombocytopenia).

Causes

Roberts syndrome is inherited as an autosomal recessive disorder. Genetic diseases of this type are determined by two abnormal genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits an abnormal version of the same gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Some cases of Roberts syndrome have had parents who were related by blood (consanguineous). All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Investigators have determined that Roberts syndrome is caused by disruptions or changes of the ESCO2 (establishment of cohesion 1 homolog 2) gene located on the short arm (p) of chromosome 8 (8p21.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes, which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further subdivided into many regions, bands and sub-bands that are numbered. For example, "chromosome 8p21.1" refers to region 2, band 1, sub-band 1 on the short arm of chromosome 8. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Certain complex chromosomal abnormalities are distinguishing features of Roberts syndrome. Most affected individuals experience premature centromere separation of various chromosomes, especially chromosomes 1, 9, and 16, a phenomenon often referred to as "puffing." The centromere is the center of a chromosome located between the long and short arms of a chromosome. The characteristic "puffing" abnormality is apparent in mitosis, the process in which a cell divides ultimately forming two cells identical to the original.

Affected Populations

Roberts syndrome affects males and females in equal numbers. The incidence of Roberts syndrome is unknown.

Related Disorders

Symptoms of the following disorders can be similar to those of Roberts syndrome. Comparisons may be useful for a differential diagnosis:

Cornelia de Lange syndrome (CdLS)
CdLS is a dominantly inherited, multi-system developmental disorder. The asymmetrical upper limb defects are similar but different from those in Roberts Syndrome (RBS), which is ranging from small hands with single palmar creases and subtle changes in the bones of fingers (phalanges) and the palm (metacarpal bones) to severe forms of lack of fingers (oligodactyly) and truncation of the forearm primarily involving the structures on "pinky" side (ulnar). The characteristic facial features seen in individuals with CdLS are easy to identify, and may be one of the most useful diagnostic signs, which includes one fused heavy eyebrow (synophrys), long eyelashes, depressed nasal bridge, long philtrum, thin upper lip, small widely spaced teeth, disproportionate small and short head (brachycephaly), and low-set ears. Other common clinical presentations are excessive bodily or facial hair (hirsutism), various eye (ophthalmologic) problems, stomach and esophagus (gastroesophageal) dysfunction, heart defects, growth retardation, and neurodevelopmental delay. The mental retardation seen in CdLS is severe, autism and self-destructive tendencies are also seen in many patients. The prevalence of this syndrome has been estimated to be approximately 1 in 10, 000, many of the mildly affected individuals may not be ascertained as having CdLS due to the phenotypic variability.

About 50% of CdLS patients have heterozygous mutations in the NIPBL genes and a small portion of patients have mutations in SMC1A or SMC3 genes, while the rest have no reported gene mutations. SMC1A and SMC3 proteins are structural subunits of the cohesin complex. Both ESCO2 (the disease causing gene of RBS) and NIPBL regulate cohesin complex, although through different mechanisms.

Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by low levels of platelets in the blood (thrombocytopenia), resulting in potentially severe bleeding episodes (hemorrhages) primarily during infancy. Other characteristic findings include absence (aplasia) of the bones on the thumb side of the forearms (radii) and underdevelopment (hypoplasia) or absence of the bones on the "pinky" side of the forearms (ulnae). Other abnormalities may also be present, such as structural malformations of the heart (congenital heart defects), kidney (renal) defects, and/or mental retardation that may be secondary to bleeding episodes in the skull (intracranial hemorrhages) during infancy. TAR syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "TAR syndrome" as your search term in the Rare Disease Database.)

Baller-Gerold syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the skull and facial (craniofacial) area and bones of the forearms and hands. In infants with Baller-Gerold syndrome, there is premature fusion of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis). As a result, the head may appear unusually short and wide and/or pointed at the top (turribrachycephaly) or relatively triangular in shape (trigonocephaly). Affected infants may also have a prominent forehead; downslanting eyelid folds (palpebral fissures); small, malformed (dysplastic), low-set ears; and/or other craniofacial abnormalities. Baller-Gerold syndrome is also characterized by underdevelopment (hypoplasia) or absence (aplasia) of the bone on the thumb side of the forearms (radii). In addition, the bone on the "pinky" side of the forearms (ulnae) is unusually short and curved and the thumbs may be underdeveloped or absent. In some cases, additional physical abnormalities and/or mental retardation may also be present. Baller-Gerold syndrome is thought to be inherited as an autosomal recessive trait, and caused by mutations in the RECQL4 gene (For more information on this disorder, choose "Baller Gerold" as your search term in the Rare Disease Database.)

Holt-Oram syndrome (HOS), also known as Cardiac-Limb syndrome, is a rare genetic disorder characterized by malformations of bones of the forearms and hands (upper limbs) and/or heart abnormalities. The thumbs may be absent (aplastic) or underdeveloped (hypoplastic) or have an extra bone (triphalangy). Additional upper limb malformations may include defects of certain bones of the wrists (carpals), the middle portion of the hands (metacarpals), the thumb side of the forearms (radii), and/or the pinky side of the forearms (ulnae). Some affected individuals also have additional musculoskeletal abnormalities, such as malformations of the bones of the upper arms (humeri), shoulder blades (scapulae), and collarbones (clavicles); other skeletal defects; and restricted range of movements at the shoulders and elbows. Characteristic heart abnormalities may include structural cardiac defects, such as an abnormal opening in the fibrous partition (septum) between the upper and/or lower chambers of the heart (atrial and/or ventricular septal defects), or abnormal transmission of electrical impulses that coordinate the heart's muscular contractions (electrocardiographic conduction defects). In some instances, other abnormalities are also present. Holt-Oram syndrome may be inherited as an autosomal dominant trait or appear to occur spontaneously due to new genetic mutations. Mutations in the TBX5 gene have been associated with HOS (For further information, choose "Holt Oram" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
A diagnosis of Roberts syndrome is suspected based upon a thorough clinical evaluation, detailed patient history and identification of characteristic abnormalities. A diagnosis may be confirmed by chromosomal analysis that detects characteristic premature centromere separation (puffing) on various chromosomes. Absence of puffing does not exclude the diagnosis, as it was reported to be absent in some clinically diagnosed cases.

In some cases, it is possible that a diagnosis of Roberts syndrome may be suspected before birth (prenatally) based upon specialized tests, such as amniocentesis, chorionic villus sampling (CVS), or ultrasonography. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal studies performed on such fluid or tissue samples may reveal premature centromere separation (puffing) in miotic cells. During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain developmental abnormalities suggestive Roberts syndrome (e.g., limb abnormalities).
The diagnosis of RBS is confirmed by molecular testing for ESCO2 mutations. The presence of mutations in this gene is strictly correlated with the centromere puffing phenomenon.

Treatment
The treatment of Roberts syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, neurologists, eye specialists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Individuals with Roberts Syndrome may benefit from surgery for facial and limb defects. Prosthetic devices can also reduce problems associated with missing limbs.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Roberts Syndrome Resources

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